Compound with indoline skeleton, and preparation method and medical application of compound

A compound, indoline technology, used in organic chemistry, antipyretics, drug combinations, etc., can solve problems such as difficulty in achieving therapeutic selectivity and specificity

Active Publication Date: 2020-07-03
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the binding properties of such activators, it is difficult to achieve therapeutic selectivity and specificity.

Method used

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  • Compound with indoline skeleton, and preparation method and medical application of compound
  • Compound with indoline skeleton, and preparation method and medical application of compound
  • Compound with indoline skeleton, and preparation method and medical application of compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Example 1: N-(M-trimethylbenzenesulfonyl))-N-(1-(1-(3-methoxyphenyl)-2-oxo-2-(phenylsulfonyl)ethyl Base) indol-4-yl) glycine (S1)

[0049] (1) 4-nitroindoline (2)

[0050] Dissolve the raw material 4-nitroindole (3.0 g, 18.5 mmol) in 20.0 mL of DCM, add 6.0 mL of trifluoroacetic acid (TFA), add 4 times the equivalent of sodium cyanoborohydride in batches under ice bath, and stir at room temperature for 4 Hour. After the reaction, add saturated NaHCO 3 Adjust the pH to nearly neutral, wash the organic layer 3 times with a saturated NaCl solution, dry over anhydrous sodium sulfate, spin to dry the solvent, and obtain 2.4 g of a red solid by column chromatography with a yield of 79%; 1 HNMR (300MHz, Chloroform-d) δ7.14 (dd, J = 8.0, 1.3Hz, 1H), 7.04 (t, J = 8.0Hz, 1H), 6.65 (dd, J = 7.9, 1.3Hz, 1H), 3.34(t, J=5.5Hz, 2H), 2.94(t, J=6.5Hz, 2H); ESI-MS m / z: 165.1(M+H) + .

[0051] (2) Methyl 2-bromo-2-(3-methoxyphenyl)acetate (4)

[0052] Dissolve raw material 3 (3g, 1...

Embodiment 2

[0066] Example 2: N-(M-trimethylbenzenesulfonyl)-N-(1-(1-(1-(3-methoxyphenyl)-2-(methylsulfonyl)-2-oxo Ethyl)indol-4-yl)glycine (S2)

[0067]

[0068] The synthesis of S2 was the same as in Example 1, replacing benzenesulfonamide with methylsulfonamide to obtain 167.0 mg of a white solid with a yield of 68%; 1 H NMR (300MHz, DMSO-d 6 )δ12.88(s,2H),8.03(s,1H),7.82(d,J=1.8Hz,1H),7.49(t,J=7.9Hz,1H),6.99(d,J=7.2Hz, 1H), 6.91(s, 1H), 6.74(d, J=10.5Hz, 2H), 6.57(d, J=8.0Hz, 1H), 6.25(d, J=7.7Hz, 1H), 5.21(s, 1H), 4.28(s, 2H), 3.73(s, 3H), 3.26(d, J=8.5Hz, 1H), 2.94(s, 3H), 2.67(d, J=8.2Hz, 1H), 2.41( s,2H),2.21(s,9H); EI-MS HRMS(ESI):found616.1735(C 29 h 34 N 3 o 8 S 2 .[M+H]+requires 616.1746).

Embodiment 3

[0069] Example 3: N-(Mes-Trimethylbenzenesulfonyl)-N-(1-(1-(1-(3-methoxyphenyl)-2-oxo-2-(trifluoromethyl) Sulfonamido)ethyl)indol-4-yl)glycine (S3)

[0070]

[0071] The synthesis of S3 was the same as in Example 1, replacing benzenesulfonamide with trifluoromethanesulfonamide to obtain 142.0 mg of a white solid with a yield of 64%; 1 H NMR (300MHz, DMSO-d 6 )12.91(s,2H),δ8.05(s,1H),7.78(d,J=1.9Hz,1H),7.29(t,J=7.9Hz,1H),6.95(d,J=7.8Hz, 1H),6.90(s,1H),6.70(d,J=10.3Hz,2H),6.56(d,J=8.0Hz,1H),6.23(d,J=7.9Hz,1H),5.20(s, 1H), 4.29(s, 2H), 3.72(s, 3H), 3.25(d, J=8.5Hz, 1H), 2.66(d, J=8.2Hz, 1H), 2.40(s, 2H), 2.21( s,9H); EI-MSHRMS (ESI): found 670.1422 (C 29 h 31 f 3 N 3 o 8 S 2 .[M+H]+requires 670.1412).

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Abstract

The invention discloses a compound with an indoline skeleton, and a preparation method and medical application of the compound. The compound containing the indoline skeleton provided by the inventioncan interfere with Keap1-Nrf2 interaction activate Nrf2 and a downstream factor, reduce cell inflammatory factors and enhance cell oxidation resistance; and therefore, the compound can reduce inflammatory injuries, has potential anti-inflammatory activity, and can be used for preparing anti-inflammatory drugs for treating inflammatory injuries caused by a plurality of inflammation-related diseases, including myocarditis, chronic obstructive pulmonary disease (COPD), Alzheimer's disease, Parkinson's disease, atherosclerosis, chronic kidney disease (CKD), diabetes, intestinal inflammation, rheumatoid arthritis and the like.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and relates to a class of Keap1-Nrf2PPI inhibitors with anti-inflammatory activity and an indoline-based skeleton, in particular to a class of compounds with an indoline skeleton, a preparation method and a medical application thereof. Background technique [0002] The human body is often attacked by some endogenous and exogenous electrophilic substances, including reactive oxygen species (ROS) and reactive nitrogen species (RNS). When cells are continuously exposed to high levels of ROS and RNS, they are placed in a state of oxidative stress. Sustained stress can impair the normal physiological functions of intracellular nucleic acids, proteins, and lipids, which can lead to a variety of related inflammatory diseases, including cancer, cardiovascular disease, and neurodegenerative diseases. To defend against these insults, cells have evolved complex cytoprotective systems that upregulate cyto...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/08C07D401/12C07D409/12A61P29/00A61P25/00A61P31/12A61P11/00A61P25/28A61P25/16A61P9/10A61P13/12A61P3/10A61P1/00A61P19/02
CPCC07D209/08C07D401/12C07D409/12A61P29/00A61P25/00A61P31/12A61P11/00A61P25/28A61P25/16A61P9/10A61P13/12A61P3/10A61P1/00A61P19/02Y02P20/55
Inventor 尤启冬姜正羽周海山陆朦辰赵静郭小可徐晓莉王磊
Owner CHINA PHARM UNIV
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